The prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. Although there are clearly strong genetic influences on susceptibility to obesity, large changes in the prevalence of obesity over recent years must reflect major changes in these non-genetic factors. Distillation of the genetic component in this complex phenotype should thus be easier to determine in children, where environmental exposure and impact has been for a relatively short period of their lifetime; in addition, obese children are more likely go on to be obese adults rather than obese adults having necessarily been obese as children. Obesity is a major risk factor for type 2 diabetes, which in turn has serious complications including accelerated development of cardiovascular disease. Given the expected global increase in the prevalence of childhood obesity, prevention of this disease and its serious complications must be addressed in order to reduce individual morbidity and the economic burden on society. Family and twin studies show that there is a significant genetic component to obesity; however, classical candidate gene studies have achieved only limited success in identifying genetic determinants of obesity and related morbidities. In light of current technological developments, this project proposes a non-hypothesis-driven study that is directed at uncovering genes and genetic variants that predispose to childhood obesity by conducting a genome-wide association (GWA) study using a high density tag-SNP array. Employing a powered two-stage study design, where cases are defined as being in the e95th percentile of BMI, we will identify association signals which we will subsequently attempt to replicate in an additional cohort. Those signals that are successfully replicated will then be tested and refined in an African American (AA) cohort, as the degree of linkage disequilibrium (LD) is lower in this ethnicity. In addition, utilizing data from AA children has the potential to help address the higher prevalence of complications of obesity in this population. Variants with equal effects in both AA and Caucasians may represent more universally important genes and pathways for diagnosis and prevention/treatment of childhood obesity and its complications. This study will be further boosted by gene- gene and gene-environment interaction considerations. PUBLIC HEALTH RELEVANCE: Obesity is a major risk factor for type 2 diabetes, which in turn has serious complications including accelerated development of cardiovascular disease; the prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. Family and twin studies show that there is a significant genetic component to obesity; however, classical candidate gene studies have achieved only limited success in identifying genetic determinants of obesity and related morbidities. This project proposes to study genetic variants that influence the pathogenesis of childhood obesity in two large pediatric cohorts by conducting a genome-wide association study using a high density tag-SNP platform.